Good day, and welcome to the Relmada Results of the Human Abuse Potential Study of REL-1017 versus ketamine call. Today's conference is being recorded. At this time, I would like to turn the conference over to Brian Ritchie of LifeSci Advisors. Please go ahead, sir. Thank you, operator, and thank you all for joining us this morning. As slide two states, please note that certain information discussed on the call today is covered under the Safe Harbor provision of the Private Securities Litigation Reform Act. We caution listeners that during this call, Relmada's management team will be making forward-looking statements. Actual results could differ materially from those stated or implied by these forward-looking statements due to risks and uncertainties associated with the company's business. These forward-looking statements are qualified by the cautionary statements contained in Relmada's press release issued today in the company's SEC filings, including the annual report on Form 10-K and subsequent filings. This conference call also contains time-sensitive information that is accurate only as of the date of this live broadcast, February 23, 2022. Relmada undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call. Now I'd like to turn the call over to the CEO, Sergio. Sergio. Thank you, Brian, and good morning, everyone. Thank you, Brian, for taking care of the Safe Harbor statement, and thanks for participating in the call today. The goal of this call is to discuss the top-line data of the second and last human abuse potential study comparison with REL-1017, with ketamine as a control. Jack Henningfield, that is, one of the top experts in the U.S. that has been advising the FDA and running these kinds of trials for 40 years, will be presenting data. I will limit myself to the introduction and a couple of opening remarks. These data have not been surprising for us. They confirm and support the previous, you know, data published about the subject of potential for abuse of REL-1017. The difference that these data have been generated with the studies according to the 2017 FDA guidance and 2022 clinical and regulatory standards. These data also support, together with the oxycodone comparison trial that we published last year in July, the DEA statement about the lack of any meaningful abuse potential for REL-1017. We do believe that the oxycodone comparative data [reduce] the risk of Schedule II potential as a schedule in the regulatory FDA and DEA. We do believe that this data, the comparison with ketamine, also reduces the risk, the potential for a Schedule III. You know, overall, the program indicates that REL-1017 will be proposed Schedule V and eventually non-schedule after the, you know, maybe one or two years of market experience. At this point with no further delays, let Jack to take over and to present the data. Thank you very much. Good morning. Thank you, Sergio. Can you hear me now? Yes. Great. Okay. I hope you can see. We will have a few slides. I am Jack Henningfield. I'm Vice President of Research, Health Policy and Abuse Liability at Pinney Associates. As Sergio mentioned, I've been conducting human abuse potential studies for more than 40 years, and that includes my years at the National Institute on Drug Abuse, where I headed Clinical Pharmacology and Abuse Potential Assessment. While at NIDA, I worked with the DEA and the FDA on drug scheduling issues. The human abuse potential or HAP study that we are presenting today, as Sergio mentioned, was designed according to FDA's 2017 abuse potential guidance. We had extensive input from FDA staff on the measures, the comparator, ketamine and so forth. The primary endpoint, as is typical in these studies, was a drug- liking score comparison of three doses of REL-1017 to ketamine, which was 0.5 mg/ kg intravenous. The study participants were recreational drug users with ketamine experience. Screening of the subjects, consistent with the FDA's advice, included administering placebo and 0.5 mg/ kg ketamine intravenously. We measured liking scores. If the subjects did not rate ketamine with a score of at least 65, 50 is neutral, by the way, and at least 15 points higher than placebo on the drug liking scale, then they were not qualified for the study. The point is to make sure that the subjects can respond positively to a known substance of abuse, in this case, ketamine. Such FDA recommended HAP study designs are more likely to overestimate abuse potential than to underestimate abuse potential. The primary measure was drug- liking or Emax, the maximum drug- liking. We tested three doses of REL-1017. These were the same as in the oxycodone study that we presented last year. They were the 25- mg therapeutic dose, 75 mg, which is three times the therapeutic dose, and 150 mg, which is six times the therapeutic dose and is the maximum tolerated dose. 51 subjects completed all arms of the study. These are the completer subjects. By the way, that's a little bit more than are typical for these studies. This is a well powered, well-designed study. Let's get right to the main findings. Now, I don't see a table on my screen. Hopefully, you can see a table, but if you can't, let us know. I will try to explain the results carefully. The main finding was that ketamine produced large and significant increases in drug liking. In fact, the mean ketamine score was 90 out of 100 possible points. The median for ketamine was 100. The ketamine increases were large, robust, and statistically significant. In contrast, all REL doses were substantially and significantly lower than ketamine. All doses. That includes the super therapeutic six- times dose. In fact, all of the REL-1017 doses were statistically equivalent to placebo. No REL dose was significantly greater than placebo, either by mean or median measure. As is typical in these studies, we also measured a variety of secondary measures, and that included overall drug liking, drug high, would you take the drug again, and so forth. These findings were all similar to liking in their outcome. We also included an exploratory comparison of REL-1017 versus dextromethorphan, and dextromethorphan was given at 300 mg. The results of that comparison were overall similar to those comparing REL to ketamine. That is, dextromethorphan produced robust increased liking and was statistically higher than REL. These findings, I'd like to point out, are also consistent with our animal studies, which show that REL does not engender reinforcing effects in the animal model, and it does not engender physical dependence and withdrawal in the animal models. In conclusion, these findings are also consistent with the 2009 DEA statement on S-methadone, which is as follows. As DEA said, "The d-isomer lacks significant respiratory depressant action and addiction liability." In conclusion, both the oxycodone and the ketamine HAP studies support the conclusion that REL-1017 does not have meaningful abuse potential. Thank you. I'll be happy to take questions, but I'll defer to Sergio. Sergio, take over and let me know what you would like me to answer. Thank you, Jack. I will. Operator, the data are very clear and, kind of, I would say, black and white, but we'll be happy to answer any questions from the audience. Please open the floor for the audience. Thank you. If you would like to ask a question, please signal by pressing star one on your telephone keypad. If you're using a speakerphone, please make sure your mute function is turned off to allow your signal to reach our equipment. Again, that is star one to ask a question. We'll go first to Andrew Tsai with Jefferies. Your line is open. Please go ahead. Hi, everyone. Good morning. Congrats on the data. I had two or three questions today. The first one is just on the specific AEs. Just wanted to confirm, honestly. It's just like these patients on S-methadone, even at the highest doses, you know, what specific AEs, if any, for these, maybe these outlier patients were they feeling? Can you confirm there was no euphoria, no relaxation, no withdrawal symptoms? I know you said that earlier. Maybe talk about that, and then, you know, a secondary question I have to that is, you know, my understanding is ketamine, some patients can feel, in addition to dissociation, hallucination, maybe they can feel euphoria. Is that the case here? And if so, wouldn't that reinforce the viewpoint that S-methadone indeed has, like, minimal opioid effects? Thanks. Thank you, Andrew, for the question. We have Dr. Manfredi and Dr. Pappagallo on the call that they run the study. I will let Paolo, Dr. Manfredi, to answer the question. Consider that we just got very short time ago the top line, so we won't have all the data, but clearly if there were some serious or worrisome side effects, it would have been communicated. I will let Paolo to answer the question more in detail. To answer the questions about the euphoria. Drug liking is the measure that gives you exactly what that euphoria is. We just heard from Jack that the drug liking was equivalent to placebo. I would say no euphoria here. In terms of adverse events of special interest, there might have been some cases of mild dizziness or somnolence, very temporary. But nothing to suggest abuse potential. Great. Then a follow-up question is, you know, big picture question. I mean, with all these new kind of positive data sets you've generated over the past six-12 months, you know, are there opportunities for you guys to speak to the FDA to, I don't know, gauge what they think about all of these results? I'm just curious because you do have a Fast Track designation. I noticed in the press release that, you know, you intend to share the results or submit the results to the FDA. So a little more clarity on that would be helpful. Thanks. Yeah, sure. Thank you, Andrew. Well, the plan is to discuss with the FDA in a meeting probably happening sometime in mid-year. You know, with the goal of being sure that we have done everything that you know we are supposed to do to show the lack of meaningful abuse potential. We follow the 2017 FDA guidance by the book. But you know we want to be sure. Consider that the FDA does not, right, consider top line satisfactory for discussion. We will have to wait for the final report of the ketamine data. We just received the oxycodone final report. When we have all the package, we'll file with the FDA, and hopefully they will accept to discuss. Don't expect any indication on the potential scheduling. The scheduling will be up to the DEA, but clearly the FDA recommendation is very important. You know, the goal is really just to be sure that, you know we have done everything that satisfy the FDA to show the lack of abuse potential, meaningful abuse potential for REL-1017. Okay, thanks. Thank you very much. I think I'll let the other colleagues ask questions. Thank you. Thank you, Andrew. Our next question comes from Yatin Suneja at Guggenheim Partners. Your line is open. Please go ahead. Hey, guys. Thanks for taking my question. Just a similar question to what Andrew was asking earlier. Is there a mechanism where you can engage with DEA prior to the approval to get their gauge on, you know, whether it's IV or V from scheduling perspective? And can you also just talk about how does it actually work? Like, you propose schedule V for them, and then you go back and forth? I have one more question. Yeah. Thank you, Yatin. I will let Jack answer the second part of the question about how the process works and what we would, you know, propose the schedule V. In terms of, you know, feedback from the FDA or the DEA, it's unlikely they will make any statement before the FDA will give them their advice or their suggestion. We are engaging with the DEA just to be sure that they know us and, you know, they become familiar with the data. But we don't expect anything clear or any clear indication before, you know, the FDA provide recommendation to the DEA. Jack, would you mind to take the question about, you know, the process, how it works and what we will propose the scheduling as a Schedule V and why? Yes. The process actually is much more orderly since the Improving Regulatory Transparency for New Medical Therapies Act went into effect in 2016. If you'd like more information on that, you can Google the Improving Regulatory Transparency for New Medical Therapies Act. In a nutshell, what that says is that FDA takes the lead on the scheduling recommendation. DEA has 90 days to finalize the schedule with an interim final recommendation. Since that went into effect, in every case, DEA has met its timeline and has provided the same schedule that FDA has recommended. DEA finalizes it, but they follow FDA's lead unless DEA has a very good reason for delay or difference, and that has not occurred. In this case, our findings are saying exactly what DEA itself concluded several years ago. I don't expect any hang up with DEA. I expect the process to move efficiently as it has over the last five years. DEA will be informed of the results ahead of time, so it will not be a surprise to them. The studies from oxycodone, the animals have already been presented publicly and will be presented to DEA, and the same with the ketamine study. The ketamine study will also be presented at public meetings. This is a relatively straightforward process these days. Got it. Thank you. Can you just confirm the formulation that was used in this study for REL-1017? Any different from the ongoing studies? Can you also tell us more the timeline or confirm the timeline for the upcoming monotherapy results? Thank you so much. Thank you, Yatin. Yeah, the formulation is exactly the same that we are using in phase III. It is you know the one that will become the commercial formulation is 25- mg tablets, and for the 150 mg they put six tablets in a capsule, so it was double masking. The timing of the phase III study are enrolling and we are planning to have data in second half of the year. Monotherapy probably may come even little earlier than mid-year. We'll be more precise you know in a month or two when you know when we get more advanced in the enrollment. The plan is to have data this year. Very good. Thank you so much. We'll go next to Joon Lee with Truist Securities. Your line is open. Please go ahead. Hi. Thanks for taking our questions, and congrats on the positive data. Did I hear you correctly about including an exploratory dextromethorphan arm? What was the rationale for including this? You know, what are the implications of this result? I have a follow-up. Well, thank you, Joon. Yes, we did include dextromethorphan 300 mg in the study. The goal was, let me give you a little bit of background. The dextromethorphan comparison is not part of the FDA filing and will not have any impact on the scheduling of the drug. That's why we did not put it in the press release or in the presentation. It's an exploratory endpoint and the goal is that we have in development certain number of derivatives of REL-1017 with the same chemical structure, but with some change. You know, since dextromethorphan has a very similar mechanism of action, we wanted to be sure that at least on the likability part, to have some data that we can use. I would not read anything else in, you know, the dextromethorphan endpoints, except that we will present detailed data. I believe in June there is a conference in Minneapolis, the College on Problems of Drug Dependence, where we will present more detailed data. You know, the good part is that, as Jack mentioned, the REL-1017 is statistically different from dextromethorphan on likability. Dextromethorphan is more likable, and it is an over-the-counter drug. I would leave it like that. Right. Which is really, I think interesting given that dextromethorphan is not scheduled, right? Okay. Were you- I wanna be clear. This is not going to be part of the FDA discussion or filing regarding the schedule for REL-1017. It was an exploratory endpoint that we wanted to, you know, for our own scientific and clinical information. Got it. Can you confirm whether the FDA was okay with the IV ketamine as a comparator as opposed to oral ketamine at a higher dose? Were there any mechanisms in place to mask the effects of IV infusion? Yes. No, the FDA was clearly okay with the IV ketamine. This is the same protocol and the same dose of ketamine that was used in the SPRAVATO esketamine trial. The intravenous 5 mg/ kg in 40 minutes infusion. That's pretty much the standard of the ketamine comparison. The FDA w as on board with that. Got it. One last question. You know, not to nitpick at the data, but when you presented the oxycodone data, the P values were less than 0.001 across the board. But today, the P values are less than 0.01. I think they're fine, but just curious if there you saw a little bit more variability in the IV ketamine study, HAP study. Yeah. Thank you, Joon. No, we did not. We just did it for simplicity. Since the statistical plan is set for -0.05, we just decided to make it simple. The P values they are, right, they're different from one another. I believe most of them, they are below 0.001. It was just simplicity p resenting the data. Got it. Thank you. Congrats on the data. Thank you, Joon. We'll go next to Marc Goodman, SVB Leerink. Your line is open. Please go ahead. Hey, thanks for taking my question. This is Rudy on the line for Marc. Congratulations on the data. Can you remind us what other safety studies are required by the FDA? What will be the gating factors for filing if you get positive data from the pivotal trials later this year? Lastly, I have one more question. Can you remind us about the difference between the modified completer population versus the total completers? Thanks. Sure. Well, thanks for the question. Let me answer first the second question that is important, the difference between the modified and the full completers. These data are, you know, all comers, so is the full completers. That's what the 2017 guidance states. In the oxy trial, we did present the modified completer for the simple reason that we did not have the completer population. We put the data out very quickly as you can see also for ketamine, but this time we had statistician to provide both measures. The 2017 guidance looks at all completers. The modified completers is a little bit of an artifact where the patients that respond to placebo, they are excluded. There was one patient in this study, and there were three subjects in the oxycodone study. The modified and the full completers for the ketamine data are exactly the same. For the oxycodone, there is a difference. There are three subjects that responded to placebo. If we include the three subjects that responded to placebo, then REL-1017 is statistically equivalent to placebo also in the oxycodone study. I hope I answered your question. We will publish the data as well for the completers in the oxycodone study. Got it. That's very helpful. There was another part of your question. I was just asking about what other safety study is required by the FDA and what are gating factors for filing? For the 2017 abuse program, we are done. We'll discuss with the FDA if there is any need to do anything more, but we did in- vitro, we did animal, and we did the two large human studies. That's it, unless the FDA wants something additional. In terms of safety study for filing the NDA, we are not required, as we published last year, to do any two-year carcinogenicity study, no QTc interval prolongation study. We are running the standard special population, renal, hepatic, and we don't need to do a food effect study. There is no food effect for REL-1017. They all will be completed before, you know, we file the NDA. Probably the last one to be completed will be the open label 12-month safety study that is up and running, but it takes 12 months, so that will be the last study. We have a rolling NDA, so that would probably be the last study, part of the rolling NDA. The plan is, you know, will be more specific later on in the year, but the plan would be to file the NDA sometime in mid-2023. Got it. Thanks, and congratulations on the data. Thank you. Regards to Marc. We will go next to Vamil Divan at Mizuho Securities. Your line is open. Please go ahead. Great. Thanks for taking my questions, and thanks for hosting the call. Just two sort of follow-up questions. One going back to the exploratory work you did around dextromethorphan. Can you discuss why you studied against a 300- mg dose? I'm just curious, why not higher or lower? I just don't know enough to understand why you picked that dose. And then the second question I have, and I think this may have been asked a little bit before, but just as you look, and I guess this might be more for Jack, but as you look at sort of the maximally- tolerated dose, you do see a sort of a trend towards it starting to separate. It's obviously still not specifically distinct from placebo. But I'm just curious if there's any concerns. We saw that also with the oxycodone data where you know the 150mg started showing a little bit of a trend. I'm wondering, is that something that Jack thinks you know could raise any concerns of any kind with DEA or FDA? Thank you. Thank you, Vamil. I'll let Paolo too, to answer the dose of the dextromethorphan, the 300 mg. There is a couple of specific reasons. Paolo will address them. The dextromethorphan dose is an in-between dose among the doses described by the DEA in a monograph that do have some psychoactive effects. We did not pick the highest dose, which is above 500 mg, and we did not pick the lowest dose, which is around 200 mg. We picked something in between. There was a recent study comparing dextromethorphan with psilocybin, and there they used 400 mg. We were more conservative than that. We used a bit of a lower dose. I hope that answers your question. Yeah. Vamil, if I can add, the 300 mg is about six times the daily therapeutic dose of dextromethorphan as a cough medication. We try also to match six times therapeutic dose of REL-1017 versus six times dextromethorphan. I hope, yeah, we answered your question. Jack, would you mind to take the second one? No, I think you summarized it well. It was actually my colleagues at Johns Hopkins who did the 400- mg comparison with psilocybin. The idea is to have a robust positive comparator. You know, it could have been 400 mg, it could have been higher, it could have been a little lower. 300 mg is what I would consider to be a robust comparator and makes a good comparison dose for such a study. Right. Jack, I believe Vamil was also asking about maximum tolerated dose and the effect and the trend in likability. Yes. The dextromethorphan produced robust significant increase in liking and— I think, Jack, was REL-1017, not dextromethorphan, was our drug. Vamil, maybe you may want to repeat the question. Yeah. Yeah, the question was just on the, you know, when we look at the three different doses of 1017, we saw this in the oxycodone trial and now again in this one where there's just a little bit of a trend, maybe almost a dose response in terms of likeability as you go from 25 mg to 75 mg to 150 mg. I'm just wondering, obviously, it's still not statistically separate from placebo here. It was a little bit in or was, I think the P value is like 0.08 in the oxycodone trial. I'm just wondering if that may raise any concerns even though it's still clearly distinct from what we see with the comparator with oxycodone or ketamine. Just curious on that. Jack. I could, Sergio, could you repeat the main part of that question because it was a little quick and light in my headphones. Yeah. I believe Vamil would like to expand and to ask if the maximum tolerated dose of REL-1017 that there is, you know, is statistically equivalent to placebo, but it, the score is higher. If you read anything on that. Am I correct, Vamil? Yes. Yeah. Not at all. That's typical. The variability overall for placebo was quite low, as is expected in these sorts of studies. When you go to super high doses, and we call them super therapeutic, actually the three times as a super therapeutic dose, there is very little visual increase. There's a little bit more variability at the six- times dose, and remember that's at a dose that is maximum tolerated. To put it simply, people can feel something. That doesn't necessarily mean that it's robust- liking, and it wasn't not robust- liking. When people can feel something, they often respond with something that we can see. There are some subjects that had a slightly elevated response, but overall, it is not statistically different from placebo. This is pretty consistent with studies that I've been involved in over the decades. Okay. Thank you. We'll go next to Jay Olson with Oppenheimer. Your line is open. Please go ahead. Oh, hey, guys. Congrats on these results, and thank you for taking the questions. Can you talk about how these results differentiate REL-1017 from your competitors that do have abuse liability potential, and how do you plan to leverage that differentiation for clinical and commercial advantages? Right. Good morning, Jay. I believe you're referring to esketamine that is, I believe, the only competitor that has a that is a Schedule III. The scheduling and the abuse potential is only one of the differences. In this case, you can clearly see that esketamine has a very similar profile to ketamine. It's speculative, but if you will run the study with esketamine instead of ketamine, probably the result would not be very different from what we have seen with ketamine. That's one difference, but there are other difference that includes, you know, the hospital, not oral availability, the administration of esketamine in clinic. You have to go to the clinic twice a week for the first month, and you have to stay there for two or three hours minimum. You cannot drive for 24 hours. There is several differences and including also the side effect profile. The absence of, you know, the psychotomimetic effect of REL-1017, it's an important factor. What we do believe we have in common is the efficacy, but everything else, it looks pretty different. Do you expect that difference to translate into significant clinical and commercial advantages? Well, we do. We clearly do. It's a once- a- day tablet, as tolerated as a placebo, 25 mg. With a comparable, if not superior, efficacy that of course we will have to prove in phase III. Based on the phase II, clearly the efficacy signal for REL-1017 is, it's very strong. We don't expect to have any ramps. I believe it's public information that in the long-term safety study, it's an outpatient. The phase III is all outpatients, and in a long-term safety study, patients go home with 30 tablets in a bottle. We have no reported issues of anybody trying to take more than a tablet or, so we feel pretty good. If this data, the phase II, will be confirmed, as we hope and expect, in phase III, the profile is for best- in- class for this new class of drug. Great. That's helpful. Maybe just to follow- up on the dextromethorphan arm. Does that also provide some points of differentiation versus your competitors? I would say no. Dextromethorphan is a closed chapter. I believe Jack was part of the team that discussed the dextromethorphan non-scheduling and over-the-counter status in the past. Dextromethorphan, you know, the FDA is pretty comfortable with the current status. So we don't. I know you're referring to AXS-05, I believe. No, I don't think there is any issue with the abusability or with scheduling for dextromethorphan in the FDA mind. No, that's not going to be the differentiation factor. We don't believe so. Okay. All right, great. Thank you very much. Thank you, Jay. Once again, ladies and gentlemen, it is star one if you have a question or comment. We will go next to Andrea Tan with Goldman Sachs. Your line is open. Please go ahead. Hi. Thanks. This is Matt on for Andrea. Can you remind us where you stand with discussions with the FDA and if you have alignment that these two studies are sufficient to conclusively answer the question on 1017 's abuse potential? Thank you. Thank you for the question. Yes, we do believe that this completes the whole program. We followed the 2017 guidance by the book, so we don't expect to do anything more. We have in- vitro data generated last year. We have animal data that we have presented there, and they are very clean. Now we have two large human abuse studies. So we do believe it's probably it's the most extensive abuse potential program that has been run by a company so far. Jack can have more insight into that, but I think we did everything we were supposed to do. I really have nothing to add. We've worked closely with the FDA and done everything that they've asked. The data are strong and clear. This is relatively straightforward as scheduling issues go from my perspective. Great. Thank you. Thank you, Jack. With no other questions holding, I'll turn the conference back to Sergio for any additional or closing comments. Thank you. Well, thank you all for participating in the conference. We are always available if there is any further question. For now, I wish everyone on the call a wonderful rest of the day. Thank you. Ladies and gentlemen, that will conclude today's call. We thank you for your participation. You may disconnect at this time.